Highlights
- Among 52,850 veterans with newly diagnosed HFrEF, only 21.2% achieved quadruple guideline-directed medical therapy (GDMT) over a median follow-up of 2.9 years.
- The median time to quadruple therapy (TTQ) was 197 days (approximately 6.5 months), highlighting significant delays in treatment optimization.
- Prescription copays emerged as a modifiable barrier, associated with an 8% lower rate of achieving quadruple therapy compared to patients with no copay requirements.
- Racial and ethnic minority patients paradoxically achieved quadruple therapy faster than White patients, suggesting potential differences in care engagement or disease severity at presentation.
Background: The Imperative for Optimal Medical Therapy in HFrEF
Heart failure with reduced ejection fraction (HFrEF) remains a leading cause of cardiovascular morbidity and mortality worldwide, affecting approximately 6.5 million adults in the United States alone. Over the past decade, the therapeutic landscape of HFrEF has undergone a remarkable transformation with the introduction of multiple disease-modifying medications that target distinct pathophysiological pathways. The cornerstone of contemporary HFrEF management rests upon quadruple guideline-directed medical therapy (GDMT), comprising four pharmacologic pillars: beta-blockers, renin-angiotensin system inhibitors (including ACE inhibitors, ARBs, or ARNI), mineralocorticoid receptor antagonists (MRAs), and the newer sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors).
Evidence from landmark randomized controlled trials has conclusively demonstrated that simultaneous implementation of these four drug classes yields substantial reductions in heart failure hospitalizations, cardiovascular mortality, and all-cause mortality. Despite this robust evidence base, translating these findings into routine clinical practice has proven challenging. Prior studies have documented significant underutilization of GDMT components, particularly among patient subgroups facing socioeconomic barriers or those with comorbidities such as chronic kidney disease. However, contemporary data characterizing the temporal dynamics of therapy initiation and the specific factors influencing time to achieve complete quadruple therapy have remained limited.
Study Design and Population
This retrospective cohort study utilized data from the Veterans Health Administration (VHA) database, representing one of the largest integrated healthcare systems in the United States. The study population included patients with incident HFrEF diagnosed between January 1, 2020, and December 31, 2023, with data analyses conducted from November 2024 through December 2025.
The study cohort comprised 52,850 patients with newly diagnosed HFrEF. The median age was 71.8 years (SD 11), reflecting the typical demographic of the veteran population. The cohort was predominantly male (97%, n=51,473), with racial and ethnic composition including 20% Black patients (n=10,791), 5% Hispanic patients (n=2,528), 68% White patients (n=35,867), and 7% from other racial or ethnic groups (n=3,664).
The primary exposure variables included race and ethnicity, sex, and prescription copay status stratified by priority group. Secondary exposures encompassed clinical characteristics including diabetes mellitus, chronic kidney disease (CKD), and the setting of HFrEF diagnosis (inpatient versus outpatient). The primary outcome was achievement of quadruple therapy, defined as concurrent use of all four evidence-based medication classes according to pharmacy fill data, with time to quadruple therapy (TTQ) calculated as the first date when all four medication classes overlapped based on dispense date and days’ supply.
Key Findings
Overall Achievement of Quadruple Therapy
The most striking finding of this study was the low overall rate of quadruple therapy achievement. Among 52,850 patients with incident HFrEF, only 11,217 (21.2%) achieved quadruple therapy over a median follow-up period of 2.9 years (IQR 1.9-3.9 years). This finding underscores a substantial gap between guideline recommendations and real-world implementation, with the vast majority of patients remaining suboptimally treated despite the proven mortality benefits of complete GDMT.
Time to Quadruple Therapy
Among those who achieved quadruple therapy, the median time to achieve all four medication classes was 197 days (IQR 49-528 days), corresponding to approximately 6.5 months. This median TTQ indicates that even among patients who eventually reached the treatment target, significant delays persisted. The wide interquartile range (49-528 days) highlights substantial variability in the speed of therapy optimization, with some patients achieving quadruple therapy within weeks while others required more than a year and a half.
Racial and Ethnic Differences in TTQ
Contrary to what might be expected given well-documented disparities in cardiovascular care, the study found that racial and ethnic minority patients achieved quadruple therapy more rapidly than White patients. After adjustment for potential confounders, Black patients demonstrated a 22% higher rate of quadruple therapy achievement compared to White patients (hazard ratio [HR], 1.22; 95% CI, 1.15-1.30). Similarly, Hispanic patients had a 21% higher rate (HR, 1.21; 95% CI, 1.09-1.33), and patients from other racial or ethnic groups demonstrated an 11% higher rate (HR, 1.11; 95% CI, 1.02-1.20).
While these findings may appear paradoxical in the context of known healthcare disparities, several potential explanations merit consideration. Minority patients may present with more advanced or symptomatic disease requiring more aggressive pharmacotherapy. Additionally, the VHA system provides relatively equitable access to healthcare services, potentially mitigating some external barriers to care that exist in other healthcare settings. Alternatively, these results may reflect survival bias, whereby minority patients with more severe disease who survived long enough to achieve quadruple therapy were selectively captured in the analysis.
Sex Differences in TTQ
The study found no significant difference in time to quadruple therapy between female and male patients (HR, 0.97; 95% CI, 0.86-1.09). Although women represented only 3% of the study cohort, the comparable TTQ between sexes suggests equitable implementation of GDMT once HFrEF was diagnosed, at least within the VHA healthcare system. However, the small proportion of female patients limits the statistical power to detect smaller effect sizes and warrants caution in interpreting these null findings.
Impact of Prescription Copays
Perhaps the most clinically actionable finding was the association between prescription copays and achievement of quadruple therapy. Patients with prescription copay requirements (priority groups 2-8) experienced an 8% lower rate of achieving quadruple therapy compared to patients with no prescription copay requirements (priority group 1) (HR, 0.92; 95% CI, 0.87-0.96). This finding identifies medication cost as a significant modifiable barrier to optimal HFrEF management and suggests that reducing or eliminating prescription copays for essential GDMT medications could improve treatment uptake and, potentially, clinical outcomes.
Clinical Characteristics and TTQ
Several clinical factors were associated with differential rates of quadruple therapy achievement. Patients diagnosed with HFrEF in the outpatient setting demonstrated higher rates of quadruple therapy compared to those diagnosed during inpatient hospitalization (22.2% versus 14.2%, respectively). This finding likely reflects the challenges of initiating and titrating GDMT during acute illness when patients are hospitalized, as well as the competing priorities of managing acute decompensation versus long-term disease-modifying therapy.
Comorbid diabetes mellitus was associated with higher rates of quadruple therapy achievement (23.6% versus 19.3% in patients without diabetes). This association may reflect more frequent healthcare encounters among diabetic patients, greater awareness of cardiovascular risk, or earlier initiation of cardioprotective medications such as SGLT2 inhibitors that have dual benefits in both conditions.
Conversely, the presence of chronic kidney disease was associated with lower rates of quadruple therapy achievement (22.5% versus 18.1% in patients without CKD). This finding highlights the ongoing challenge of GDMT optimization in patients with renal impairment, where concerns about hyperkalemia, reduced GFR, and polypharmacy may lead to therapeutic inertia or intentional underutilization of evidence-based therapies.
Expert Commentary and Clinical Implications
The findings of this study illuminate the persistent gap between guideline recommendations and clinical practice in HFrEF management. With only one in five patients achieving quadruple GDMT over nearly three years of follow-up, there remains substantial room for improvement in treatment optimization. The median TTQ of approximately 6.5 months, while seemingly reasonable on the surface, masks considerable variability and may be unacceptably long for patients at highest risk of adverse outcomes.
The identification of prescription copays as a modifiable barrier carries important health policy implications. Given the strong evidence supporting mortality reduction with GDMT, policies that reduce financial burdens on patients for essential heart failure medications could yield substantial public health benefits. This aligns with emerging payer initiatives to eliminate cost-sharing for high-value cardiovascular medications and suggests a potential avenue for quality improvement interventions.
The paradoxical finding of faster quadruple therapy achievement among racial and ethnic minority patients merits careful interpretation. While these results may suggest more equitable care within the VHA system compared to other healthcare settings, they should not obscure the well-documented existence of structural barriers to cardiovascular care affecting minority populations. Future research should investigate the mechanisms underlying these observed differences and ensure that any quality improvement initiatives do not inadvertently widen existing disparities.
The study’s limitations include its retrospective design, which precludes causal inference, and its restriction to the veteran population, which limits generalizability to broader patient populations. Additionally, the use of pharmacy fill data to define medication exposure may not fully capture actual medication adherence or clinical appropriateness of therapy. The predominantly male cohort also restricts conclusions regarding female patients with HFrEF.
Conclusion
This large retrospective cohort study of 52,850 veterans with incident HFrEF reveals substantial opportunities to improve both the rate and timeliness of quadruple guideline-directed medical therapy. With only 21.2% of patients achieving complete GDMT over nearly three years and a median time to therapy of 197 days, significant gaps persist between evidence and practice. The identification of prescription copays as a modifiable barrier provides a clear target for intervention, while the differential achievement of therapy based on diagnosis setting and comorbidities highlights populations that may benefit from targeted quality improvement initiatives. Addressing these gaps in HFrEF management represents an urgent priority for improving cardiovascular outcomes in this high-risk population.
Funding and Disclosures
This study utilized data from the Veterans Health Administration database. The original study was published in JAMA Cardiology on April 1, 2026 (PMID: 41920552). Specific funding sources and potential conflicts of interest should be referenced from the original publication.
References
- Jacobs JA, Greene T, Vanneman ME, et al. Time to Quadruple Therapy After Initial Diagnosis of Heart Failure With Reduced Ejection Fraction. JAMA Cardiol. 2026. PMID: 41920552.
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